Neurodevelopmental diseases like schizophrenia are common, complex genetic disorders that affect higher cognitive function, and exact a high burden on individuals and society. The developmental environment has also been shown to increase disease risk, for example intrauterine infection, nutritional deprivation and urban living However, little is known about which genes interact with different environments to influence higher cognitive brain process known to be associated with heritable risk for disease. Thus, the goal of this collaborative US-China study is to leverage China's exceptional naturalistic research opportunities to powerfully examine the effects on higher brain functions of starkly different degrees of rural and urban childhoods resulting from China's unique economic development, and how these may influence genetically controlled higher-cortical functions linked with disease, within its population of relatively limited ancestral diversity. In Aim 1, we will define, using functional MRI, prefrontal- striatal-hippocampal circuit intermediate phenotypes associated with heritable risk for schizophrenia in a twin study, supplemented by neuroimaging data from patients and siblings. We will also define the effects of differing degrees of childhood urban or rural environments on these intermediate phenotypes in adult individuals, controlling for IQ, socioeconomic status and genetic heterogeneity. In Aim 2, using a candidate gene and genome-wide strategy, we will examine specific gene-environment interactions based on the brain phenotypes associated with heritable risk for schizophrenia and sensitive to the environment in Aim 1. These associations will be further interrogated in available genome-wide association datasets, and in terms of prefrontal and hippocampal postmortem brain expression profiles across the human lifespan. At the end of the study, we will have defined the influence of childhood rural or urban upbringing on higher brain functions implicated in heritable risk of schizophrenia, and putative genetic influences on these environmental brain effects. This will enhance knowledge about how modifiable aspects of the childhood environment and potentially novel genetic disease mechanisms biases towards risk or resilience for schizophrenia.